Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia

Guido Marcucci, John C. Byrd, Guowei Dai, Marko I. Klisovic, Peter J. Kourlas, Donn C. Young, Spero R. Cataland, Diane B. Fisher, David Lucas, Kenneth K. Chan, Pierluigi Porcu, Zhong Pin Lin, Sherif Farag, Stanley R. Frankel, James A. Zwiebel, Eric H. Kraut, Stanley P. Balcerzak, Clara D. Bloomfield, Michael R. Grever, Michael A. Caligiuri

Research output: Contribution to journalArticle

185 Citations (Scopus)

Abstract

Overexpression of Bcl-2 is a potential mechanism for chemoresistance in acute leukemia and has been associated with unfavorable clinical outcome. We hypothesized that down-regulation of Bcl-2 would restore chemosensitivity in leukemic cells. To test this hypothesis, we performed a phase 1 study of G3139 (Genasense, Genta, Berkeley Heights, NJ), an 18-mer phosphorothioate Bcl-2 antisense, with fludarabine (FL), cytarabine (ARA-C), and granulocyte colony-stimulating factor (G-CSF) (FLAG) salvage chemotherapy in patients with refractory or relapsed acute leukemia. Twenty patients with refractory or relapsed acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) were enrolled. G3139 was delivered by continuous infusion on days 1 to 10. FLAG chemotherapy was administered on days 5 to 10. Common side effects of this combination included fever, nausea, emesis, electrolyte imbalance, and fluid retention that were not dose limiting. Plasma pharmacokinetics of G3139 demonstrated steady-state concentration (Css) within 24 hours. Of the 20 patients, 9 (45%) had disease response, 6 (5 AML, 1 ALL) with complete remission (CR) and 3 (2 AML and 1 ALL) with no evidence of disease but failure to recover normal neutrophil and/or platelet counts or to remain in remission for at least 30 days (incomplete remission). Bcl-2 mRNA levels were down-regulated in 9 of the 12 (75%) evaluable patients. This study demonstrates that G3139 can be administered safely with FLAG chemotherapy and down-regulate its target, Bcl-2. The encouraging clinical and laboratory results justify the current plans for a phase 3 study in previously untreated high-risk AML (ie, age at least 60 years).

Original languageEnglish
Pages (from-to)425-432
Number of pages8
JournalBlood
Volume101
Issue number2
DOIs
StatePublished - Jan 15 2003
Externally publishedYes

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Pharmacodynamics
Chemotherapy
Antisense Oligonucleotides
Combination Drug Therapy
Refractory materials
Leukemia
Acute Myeloid Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Drug Therapy
Down-Regulation
Salvaging
Pharmacokinetics
Cytarabine
Granulocyte Colony-Stimulating Factor
Platelets
Platelet Count
Nausea
Electrolytes
Vomiting
Neutrophils

ASJC Scopus subject areas

  • Hematology

Cite this

Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia. / Marcucci, Guido; Byrd, John C.; Dai, Guowei; Klisovic, Marko I.; Kourlas, Peter J.; Young, Donn C.; Cataland, Spero R.; Fisher, Diane B.; Lucas, David; Chan, Kenneth K.; Porcu, Pierluigi; Lin, Zhong Pin; Farag, Sherif; Frankel, Stanley R.; Zwiebel, James A.; Kraut, Eric H.; Balcerzak, Stanley P.; Bloomfield, Clara D.; Grever, Michael R.; Caligiuri, Michael A.

In: Blood, Vol. 101, No. 2, 15.01.2003, p. 425-432.

Research output: Contribution to journalArticle

Marcucci, G, Byrd, JC, Dai, G, Klisovic, MI, Kourlas, PJ, Young, DC, Cataland, SR, Fisher, DB, Lucas, D, Chan, KK, Porcu, P, Lin, ZP, Farag, S, Frankel, SR, Zwiebel, JA, Kraut, EH, Balcerzak, SP, Bloomfield, CD, Grever, MR & Caligiuri, MA 2003, 'Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia', Blood, vol. 101, no. 2, pp. 425-432. https://doi.org/10.1182/blood-2002-06-1899
Marcucci, Guido ; Byrd, John C. ; Dai, Guowei ; Klisovic, Marko I. ; Kourlas, Peter J. ; Young, Donn C. ; Cataland, Spero R. ; Fisher, Diane B. ; Lucas, David ; Chan, Kenneth K. ; Porcu, Pierluigi ; Lin, Zhong Pin ; Farag, Sherif ; Frankel, Stanley R. ; Zwiebel, James A. ; Kraut, Eric H. ; Balcerzak, Stanley P. ; Bloomfield, Clara D. ; Grever, Michael R. ; Caligiuri, Michael A. / Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia. In: Blood. 2003 ; Vol. 101, No. 2. pp. 425-432.
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AU - Lucas, David

AU - Chan, Kenneth K.

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AU - Zwiebel, James A.

AU - Kraut, Eric H.

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AU - Grever, Michael R.

AU - Caligiuri, Michael A.

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N2 - Overexpression of Bcl-2 is a potential mechanism for chemoresistance in acute leukemia and has been associated with unfavorable clinical outcome. We hypothesized that down-regulation of Bcl-2 would restore chemosensitivity in leukemic cells. To test this hypothesis, we performed a phase 1 study of G3139 (Genasense, Genta, Berkeley Heights, NJ), an 18-mer phosphorothioate Bcl-2 antisense, with fludarabine (FL), cytarabine (ARA-C), and granulocyte colony-stimulating factor (G-CSF) (FLAG) salvage chemotherapy in patients with refractory or relapsed acute leukemia. Twenty patients with refractory or relapsed acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) were enrolled. G3139 was delivered by continuous infusion on days 1 to 10. FLAG chemotherapy was administered on days 5 to 10. Common side effects of this combination included fever, nausea, emesis, electrolyte imbalance, and fluid retention that were not dose limiting. Plasma pharmacokinetics of G3139 demonstrated steady-state concentration (Css) within 24 hours. Of the 20 patients, 9 (45%) had disease response, 6 (5 AML, 1 ALL) with complete remission (CR) and 3 (2 AML and 1 ALL) with no evidence of disease but failure to recover normal neutrophil and/or platelet counts or to remain in remission for at least 30 days (incomplete remission). Bcl-2 mRNA levels were down-regulated in 9 of the 12 (75%) evaluable patients. This study demonstrates that G3139 can be administered safely with FLAG chemotherapy and down-regulate its target, Bcl-2. The encouraging clinical and laboratory results justify the current plans for a phase 3 study in previously untreated high-risk AML (ie, age at least 60 years).

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